5-Lipoxygenase Pathway and Aortic Valve Stenosis

Background— The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis.

Methods and Results— After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6- and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for 5-lipoxygenase (r=–0.35; P=0.03), its activating protein (5-lipoxygenase activating protein; r=–0.39; P=0.02), and LTA4 hydrolase (r=–0.48; P=0.01) correlated inversely with the velocity–time integral ratio. In addition, leukotriene A4 hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (r=–0.52; P=0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C4 (LTC4) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification.

Conclusions— The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis.

From press release:

Research from Karolinska Institutet in Sweden shows that a specific inflammatory factor may be important in the development of the heart valve disease aortic stenosis. The results suggest that anti-inflammatory medication could be a possible new treatment.

Aortic stenosis is the most common heart valve disease, which is caused by calcium deposits and a narrowing of the aortic valve. This is typically seen in the elderly, but can also be caused by a congenital defect. Aortic stenosis is currently treated by surgical replacement of the diseased valve, but research is on-going for identifying medicines which can delay the progress of the disease.

In a new study presented in the journal Circulation, researchers from Karolinska Institutet show that specific pathways of inflammation are important underlying factors in the development of aortic stenosis.

By studying heart valves from patients undergoing surgery for various valve diseases, the researchers have shown that immune cells and a group of inflammatory substances called leukotrienes can be found in calcified heart valves. The most significant inflammation was seen in patients with the narrowest valves on ultrasound examination. The researchers have also shown in cell cultures that leukotrienes stimulate the calcification of heart valve cells.

There are similarities between atherosclerosis (calcification of the arteries) and aortic stenosis. However, lipid-lowering medicines known as statins which are capable of preventing atherosclerosis have proved ineffective in preventing calcification of the aortic valve.

"The results suggest that anti-inflammatory medication could be a future treatment for aortic stenosis, and it would mean a lot to these patients, most of whom are elderly, if we could slow the disease to the extent that they do not need surgery," says associate professor and cardiologist Magnus Bäck, one of the researchers behind the study.